Autoimmune diseases are diseases with high morbidity, whose etiology and pathogenesis are poorly understood. Self-reactive lymphocytes initiate the process of autoantibody production and ultimately lead to formation of immune complexes. Interaction of IgG immune complexes with Fc gamma receptors (FcgR) containing an activation motif initiates an inflammatory response. This pathway can be inhibited by colligation of inhibitory FcgRs. By virtue of the ability to cease cell activation, inhibitory FcgRIIb receptors can potentially modify the development or progression of autoimmune diseases by influencing either B cell or mononuclear phagocytes' responsiveness to immune complex-mediated inflammation. Targeted deletion of the FcgRIIB gene leads to severe immune complex-mediated hypersensitivity reactions and fatal autoimmunity in mice. Association of autoimmune diseases and deficiency of inhibitory FcgRllb receptors has not been reported in humans. In this proposal we present evidence that the expression and function of inhibitory FcgRIIb receptors is a highly regulated process. We have identified cytokines that reduce the expression of FcgRIIb in monocytes and B cells. In addition, we have identified novel single nucleotide polymorphisms (SNPs) in the promoter region of the inhibitory FcgRlIB in humans. These SNPs alter the transcriptional regulation of FcgRIIB in B cells and myeloid cells. In a preliminary study we have demonstrated association of FcgRIIB promoter SNPs with systemic lupus erythematosus (SLE). The specific aims are: l) to characterize acquired factors involved in the regulation of FcgRIIB gene expression; 2) to characterize the genetic alterations of FcgRIIB structure and function; and 3) to evaluate FcgRIIB as a candidate gene for SLE. Elucidating the relative contribution of acquired and genetic factors that regulate the expression of FcgRIIb function in human cells will advance our understanding of the molecular pathogenesis of autoimmune diseases and will facilitate the development of mechanism-based therapies.